Glenn Eamond Mitchell Maguire

The title compound crystallizes with one neutral Ru^II species, one cationic Ru^II species and a BF₄⁻ counter-ion in the asymmetric unit. Both Ru^II centres adopt the expected piano-stool geometry, with the η⁶-p-cymene ligand forming the seat and the chlorido and bidentate amino-alcohol-derived ligands occupying the remaining coordination sites.

In this narrative review, we assess the pathophysiology of severe adverse events that presented after vaccination with DNA and mRNA vaccines against COVID‐19. The focus is on the perspective of an undersulfated and degraded glycocalyx, considering its impact on immunomodulation, inflammatory responses, coagulation and oxidative stress. The paper explores various factors that lead to glutathione and inorganic sulfate depletion and their subsequent effect on glycocalyx sulfation and other metabolites, including hormones. Components of COVID‐19 vaccines, such as DNA and mRNA material, spike protein antigen and lipid nanoparticles, are involved in possible cytotoxic effects. The common thread connecting these adverse events is endotheliopathy or glycocalyx degradation, caused by depleted glutathione and inorganic sulfate levels, shear stress from circulating nanoparticles, aggregation and formation of protein coronas; leading to imbalanced immune responses and chronic release of pro‐inflammatory cytokines, ultimately resulting in oxidative stress and systemic inflammatory response syndrome. By understanding the underlying pathophysiology of severe adverse events, better treatment options can be explored.

Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (K_iapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log₁₀ reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

Kinetic models are essential for describing how molecules interact in a variety of biochemical processes. The estimation of a model’s kinetic parameters by experiment enables researchers to understand how pathogens, such as viruses, interact with other entities like antibodies and trial drugs. In this work, we report a simple proof-of-principle experiment that uses quantum sensing techniques to give a more precise estimation of kinetic parameters than is possible with a classical approach. The interaction we study is that of bovine serum albumin (BSA) binding to gold via an electrostatic mechanism. BSA is an important protein in biochemical research as it can be conjugated with other proteins and peptides to create sensors with a wide range of specificity. We use single photons generated via parametric down-conversion to probe the BSA–gold interaction in a plasmonic resonance sensor. We find that sub-shot-noise-level fluctuations in the sensor signal allow us to achieve an improvement in the precision of up to 31.8% for the values of the kinetic parameters. This enhancement can, in principle, be further increased in the setup. Our work highlights the potential use of quantum states of light for sensing in biochemical research.

HIV-1 protease (HIV-1 PR) is an essential enzyme for the replication process of its virus, and therefore considered an important target for the development of drugs against the acquired immunodeficiency syndrome (AIDS). Our previous study shows that the catalytic mechanism of subtype B/C-SA HIV-1 PR follows a one-step concerted acyclic hydrolysis reaction process using a two-layered ONIOM B3LYP/6-31++G(d,p) method. This present work is aimed at exploring the proposed mechanism of the proteolysis catalyzed by HIV-1 PR and to ensure our proposed mechanism is not an artefact of a single theoretical technique. Hence, we present umbrella sampling method that is suitable for calculating potential mean force (PMF) for non-covalent ligand/substrate-enzyme association/dissociation interactions which provide thermodynamic details for molecular recognition. The free activation energy results were computed in terms of PMF analysis within the hybrid QM(DFTB)/MM approach. The theoretical findings suggest that the proposed mechanism corresponds in principle with experimental data. Given our observations, we suggest that the QM/MM MD method can be used as a reliable computational technique to rationalize lead compounds against specific targets such as the HIV-1 protease. Graphical Abstract

In this study, a significantly improved method for the synthesis of modular meso-BODIPY (boron dipyrromethene) derivatives possessing a free carboxylic acid group (which was subsequently coupled to peptides), is disclosed. This method provides a vastly efficient synthetic route with a > threefold higher overall yield than other reports. The resultant meso-BODIPY acid allowed for further easy incorporation into peptides. The meso-BODIPY peptides showed absorption maxima from 495–498 nm and emission maxima from 504–506 nm, molar absorptivity coefficients from 33 383–80 434 M⁻¹ cm⁻¹ and fluorescent quantum yields from 0.508–0.849. The meso-BODIPY-c(RGDyK) peptide was evaluated for plasma stability and (proved to be durable even up to 4 h) was then assessed for its fluorescence imaging applicability in vivo and ex vivo. The optical imaging in vivo was limited due to autofluorescence, however, the ex vivo tissue analysis displayed BODIPY-c(RGDyK) internalization and cancer detection thereby making it a novel tumor-integrin associated fluorescent probe while displaying the lack of interference the dye has on the properties of this ligand to bind the receptor.

Graphical representation of the concerted acyclic transition model of an HIV-1 natural substrate using the two-layered ONIOM (B3LYP/6-31++G(d,p):AMBER) method.

Virtual screening is a useful in silico approach to identify potential leads against various targets. It is known that carbapenems (doripenem and faropenem) do not show any reasonable inhibitory activities against L,D-transpeptidase 5 (Ldt_Mt5) and also an adduct of meropenem exhibited slow acylation. Since these drugs are active against L,D-transpeptidase 2 (Ldt_Mt2), understanding the differences between these two enzymes is essential. In this study, a ligand-based virtual screening of 12,766 compounds followed by molecular dynamics (MD) simulations was applied to identify potential leads against Ldt_Mt5. To further validate the obtained virtual screening ranking for Ldt_Mt5, we screened the same libraries of compounds against Ldt_Mt2 which had more experimetal and calculated binding energies reported. The observed consistency between the binding affinities of Ldt_Mt2 validates the obtained virtual screening binding scores for Ldt_Mt5. We subjected 37 compounds with docking scores ranging from − 7.2 to − 9.9 kcal mol⁻¹ obtained from virtual screening for further MD analysis. A set of compounds (n = 12) from four antibiotic classes with ≤ − 30 kcal mol⁻¹ molecular mechanics/generalized born surface area (MM-GBSA) binding free energies (ΔG_bind) was characterized. A final set of that, all β-lactams (n = 4), was considered. The outcome of this study provides insight into the design of potential novel leads for Ldt_Mt5. Graphical abstract

The Human Immunodeficiency Virus type 1 (HIV-1) protease is a crucial target for HIV/AIDS treatment and understanding its catalytic mechanism is the basis on which HIV-1 enzyme inhibitors are developed. Several experimental studies have indicated that HIV-1 protease facilitates the cleavage of the Gag and Gag-Pol polyproteins and it is highly selective with regards to the cleaved amino acid precursors and physical parameters. However, the main theoretical principles of substrate specificity and recognition remain poorly understood theoretically. By means of a one-step concerted transition state modeling, the recognition of natural substrates by HIV-1 PR subtypes (B and C-SA) was studied. This was carried out to compare the activation free energies at varying peptide bond regions (scissile and non-scissile) within the polypeptide sequence using ONIOM calculations. We studied both P3-P3' and P5-P5' natural substrate systems. For P3-P3' substrates, excellent recognition was observed for the MA-CA family but not for the RH-IN substrates. Satisfactory recognition for the latter was only observed for the longer sequence (P5-P5') after the substrate was subjected to an MD run to maximise the interaction between the enzyme and the substrate. These results indicate that both sequence and structure are important for correct scissile bond recognition of these natural substrates.